This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this proposal, we will test the novel hypothesis that reduction of activated MMP levels (by chronic doxycycline administration) serves to restore insulin receptor integrity and improves measures of diabetes in an obese population of human subjects with DM2. Our specific aims in obese men and women with DM2 are to determine if: 1. MMP levels and activity are elevated in blood and tissue of obese subjects with DM2 compared to controls. 2. Doxycycline administered for 12 weeks suppresses MMPs to a greater extent in blood and tissue compared to placebo. 3. Insulin receptor cleavage is inhibited after treatment with doxycycline compared to placebo. 4. Doxycycline improves standard measures of diabetes compared to placebo. Our hypotheses are as follows: 1. MMP activity and insulin receptor cleavage will be greater in blood and tissue of subjects with obesity and DM2 compared to controls (Aim 1). 2. Doxycycline administration to human subjects with obesity and DM2 will decrease MMP levels and insulin receptor cleavage compared to placebo (Aims 2 and 3). 3. Doxycycline administration will improve measures of diabetes when compared to placebo (Aim 4).